Pouch with incorporated loss of integrity indicator, method for making such a bag, and method for using same

ABSTRACT

A pouch includes: a first closed, inner casing, made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a first space, forming a pouch stricto sensu for accommodating a biopharmaceutical product or device, a second closed, outer casing, made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a second space in which the pouch stricto sensu is located, spacer elements, at least one selected tracer gas, located in the first or second space outside of the pouch stricto sensu, with a higher partial pressure than in the second space outside of the pouch stricto sensu or in the first space, at least one colorimetric detector located, respectively, in the second space outside of the pouch stricto sensu or in the first space responsive to the concentration of the tracer gas, by switching from a first color to a second different color.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to the detection of a possible loss of integrityof a closed, non-porous, flexible plastic pouch, such as a sterile pouchthat is designed to accommodate a biopharmaceutical product or device orthe like.

The purpose of the invention is more especially a pouch with anincorporated loss of integrity indicator that is active per se, and,after the pouch is manufactured and at least before the time when abiopharmaceutical product or device is to be introduced thereinto, theapplication of such a pouch with an incorporated and active loss ofintegrity indicator for creating a pouch stricto sensu that has all ofits integrity and that contains the biopharmaceutical product or device,with such a pouch stricto sensu having its full guarantee of integrity,specially designed to contain a biopharmaceutical product or device, aprocess for the production of a pouch with an incorporated and activeloss of integrity indicator, and, finally, a process relative to pouchesstricto sensu that is specially designed to contain a biopharmaceuticalproduct or device and having to exhibit a full guarantee of integrity.

DESCRIPTION OF THE RELATED ART

Here, a biopharmaceutical product is defined as a product that isobtained from biotechnology—culture media, cellular cultures, buffersolutions, artificial nutrition liquids, blood products, and derivativesof blood products—or a pharmaceutical product or more generally aproduct that is designed to be used in the medical field.Biopharmaceutical device is defined as a device that is designed to beimplemented in a process of the biological or pharmaceuticalfield—measuring or checking means, means for treatment of abiopharmaceutical product, containers or parts of containers, means oftransfer or closing. Such biopharmaceutical products or devices havehigh added value, and it is important that their integrity be ensured,in particular the absence of any contamination.

For the purposes of storage or shipping, it is common to place suchbiopharmaceutical products or devices in pouches that are closed andsterile, flexible, disposable, and made of non-porous plastic (such aspolyethylene or a complex that comprises polyethylene) and that compriseat least one port or access that can be opened at the desired time.

Such pouches are known whose two large walls are directly joined to oneanother. Once expanded, such pouches have a limited volume and arerelatively thin, which justifies the fact that they are often called“pillow” pouches or “2D” (D meaning dimensions) pouches. 3D pouches arealso known that comprise two end walls and a side wall that can befolded flat and deployed unfolded, welded to one another, with thevolume then being able to be at least 50 liters up to 3,000 liters, andeven more. Such 3D pouches are described in the document WO00/04131 ormarketed by the Sartorius Company under the trademark FLEXEL® 3D.

It is essential that such pouches, once manufactured and when theyreceive the biopharmaceutical products or devices mentioned above, beairtight, or at least have a degree of sealing that is deemedsatisfactory. It is therefore essential to be able to detect anypossible loss of integrity of such pouches.

Processes and devices for checking integrity of such pouches implementedonline on all of the pouches during their manufacturing are known. Thus,the Standard F 2095-01 of ASTM International whose title is “StandardTest Methods for Pressure Decay Leak Test for Nonporous FlexiblePackages with and without Restraining Plates” relates more specificallyto the so-called pressure drop process. This process is consideredaccording to two possible embodiments, namely with or withoutexpansion-limiting plates.

In the embodiment with expansion-limiting plates, the procedure is asfollows:

-   -   In a preparation phase:        -   A pouch to be checked that has at least one port that can be            sealed or connected in an airtight and removable way is            provided,        -   A pressurized gas source that is designed to be introduced            into the pouch via the port is provided,        -   Means for measuring the pressure of the gas in the pouch via            the port are provided,        -   Two fixed expansion-limiting plates that are separated and            face one another and that will not conceal a possible leak            in the large walls of the pouch placed against them are            provided,        -   The pouch is placed flat between the two expansion-limiting            plates,        -   At least one port of the pouch is connected to the gas            source and the pressure-measuring means in such a way as to            be able to send the pressurized gas into the pouch and to            measure the pressure of the gas in the pouch,    -   And, in a subsequent test phase:        -   The pressurized gas is sent into the pouch, with the            expansion of the pouch being limited when its large walls            come against the expansion-limiting plates,        -   Then, in a subsequent stage, the pressure drop in the pouch            owing to the pressure-measuring means is compared to a            predefined pressure drop threshold of a pouch that is            considered intact.

If the pressure drop in the pouch is less than the threshold, it isconsidered that the pouch has passed the integrity check, while if thepressure drop in the pouch is greater than the threshold, it isconsidered that the pouch has not passed the integrity check.

Devices for implementing a checking process for filters and membranes,by the pressure drop technique, without expansion-limiting plates, forexample the device SARTOCHECK® 4 of the SARTORIUS Company, are known.Devices with plates from other suppliers are known. In all of the cases,such devices are complex and bulky and difficult to ship or to use atthe sites of final use of the pouches.

In contrast, an accidental rupture of the integrity of the pouch canoccur after its manufacture and before its final use, for example in thephases of storage, shipping, distribution, delivery or else in the phasethat immediately precedes the implementation of the pouch. This risk isall the greater the longer any of these phases lasts (for example, thestorage phase can reach several years) or if it involves handling of thepouch or its contact with objects that will promote damage thereof.However, such a rupture of the integrity of the pouch cannot bedecelerated by a process for checking integrity that is implementedbefore the integrity rupture takes place.

The documents U.S. Pat. No. 6,892,567 and U.S. Pat. No. 6,196,056describe processes and devices for determining the integrity of apackage or a compartment resting on the transmission of a test gasthrough the package or the wall of the compartment. This device and theassociated measuring instruments form a complex and bulky unit havingthe limitations mentioned above.

The document US 2007/0220956 describes a process and a device fordetecting a leak from a pouch designed for the production of a processthat is biological and that contains a conductive fluid, placed in arigid outer container, consisting of an electrically-operated leakdetector. Such a process and device exhibit the same limitationsmentioned above, unless they are applied in the case of a pouch that isfilled with a conductive fluid and ultimately involve the presence of arigid outer container.

The document U.S. Pat. No. 4,098,577 describes a process and anindicator for detecting the loss of integrity of transparent packagingthat contains a product that is sealed in the packaging. The packagingis filled with an artificial atmosphere such as carbon dioxide ornitrogen. A pH-sensitive detector is placed in the packaging and can beseen through it. The detector changes color in the case of a loss ofartificial atmosphere as a result of a loss of integrity of thepackaging. In the embodiments considered by the document U.S. Pat. No.4,098,577, the packaging is rigid, the product is a solid object, andthe detector is moved away from the latter. The process according to thedocument U.S. Pat. No. 4,098,577 is unsuitable in the case of packagingthat is designed to accommodate a fluid product coming into contact withthe detector. In addition, the document U.S. Pat. No. 4,098,577 neitherdescribes nor suggests, indeed quite the contrary, that the detectiontakes place before the product is placed in the packaging.

The document U.S. Pat. No. 4,813,541 describes a process and packagingwith a tamper-proof indicator. The packaging comprises a firsthermetically sealed, rigid, inner container filled with a firstatmosphere and containing a substance, and a second hermetically sealed,rigid, outer container in which there is located—in a spaced positionowing to crosspieces—the first container, the inner cavity of the secondcontainer outside of the first container being filled with a secondatmosphere at a pressure that is different from that of the firstatmosphere, and detection means being placed in the cavity and beingsensitive to a modification of the second atmosphere due to a rupture ofintegrity of the first container or the second container. The documentU.S. Pat. No. 4,813,541, which describes a very particular structure,does not suggest that the detection take place before the substance isplaced in the first container.

The document WO 01/04624 describes a colorimetric system that comprisesa detector that is sensitive to carbon dioxide.

The document WO96/12659 describes a so-called tamper-proof packagingthat comprises an inner membrane that delimits an inner compartment,which contains a first medium that consists of air, as well as an outermembrane that delimits an outer compartment that surrounds the innercompartment and contains a second medium that consists of carbondioxide. An indicator tab, sensitive to the surrounding environment, isprovided inside the outer compartment, and it can give an indicationrelative to a change in the first medium and in the second medium.

The document U.S. Pat. No. 4,434,893 describes a packaging foraccommodating products that comprise inner and outer cases. In oneembodiment, the inner case and the outer case respectively have only asingle flexible wall, and these inner and outer cases are pressurizedusing a gas that has a pressure that is higher than the atmosphericpressure in such a way as to inflate their flexible wall. In anotherembodiment, the two walls of each of the inner and outer cases areflexible. The products—capsules, gel capsules or the like—to beprotected are included inside the inner case, and the inner case isitself located in this outer case in such a way as to form a protectionpreventing access to the products.

The document U.S. Pat. No. 4,436,203 describes a packaging thatcomprises an inner container of predefined size, filled with a productand pressurized before being arranged inside an outer container. Afterits inner pressure has dropped below the atmospheric pressure, saidouter container is closed. Thus, when one of the walls of the packagingis pierced, the consumer is alerted because the product may have beentouched.

The document FR 2 252 619 describes a device that is designed to be usedwith a packaging that is normally closed hermetically. It comprises adetector that is arranged in such a way that it is in communication withthe interior of the packaging but also visible from the outside. Thisdetector contains a pH-sensitive dye, which has a first color at anormal atmospheric pH and a second color at a pH that is slightlygreater than or less than the normal atmospheric pH.

The invention therefore has as its object to eliminate theabove-mentioned problems by proposing to detect the rupture of integrityof a pouch—at any desired time after its manufacture and in any casejust before its use by installation in the pouch of contents that can befluid and that come into contact with the inner surface of the pouch—ina reliable, easy and quick way, without the necessity for a heavy orcomplex dedicated device, or difficult or delicate operations, withoutthe necessity of having to resort to specialized personnel especiallyand exclusively dedicated to checking the integrity, and without thenecessity of having to test the pouch positively to ensure itsintegrity, the loss of integrity being revealed automatically andtherefore without the necessity, when the pouch is part of a largenumber of pouches, of having to test each pouch positively.

BRIEF SUMMARY OF THE INVENTION

For this purpose, according to a first aspect, the purpose of theinvention is a pouch with an incorporated loss of integrity indicatorthat is active per se and after the manufacturing of the pouch and atleast before the time when a biopharmaceutical product or device is tobe introduced thereinto,

-   -   Comprising:        -   A first flexible, closed, inner casing, made of at least one            non-porous plastic material with a high-capacity gas            barrier, delimiting a first space, forming a pouch stricto            sensu that can accommodate the biopharmaceutical product or            device when desired but devoid of the latter, comprising, on            the one hand, first introduction means for the purpose of            subsequent introduction, when desired, of the            biopharmaceutical product or device into the pouch stricto            sensu, and, on the other hand, first evacuation means for            the purpose of subsequent evacuation, when desired, of the            biopharmaceutical product or device of the pouch stricto            sensu, with the first introduction means and the first            evacuation means being in the inactive closed state,        -   A second closed, outer casing made of at least one            non-porous plastic material with a high-capacity gas            barrier, delimiting a second space in which the pouch            stricto sensu is located for the purpose of the detection of            a possible loss of integrity of the latter, comprising, on            the one hand, second introduction means that made possible            the preliminary introduction of the pouch stricto sensu in            the second space, and, on the other hand, second evacuation            means for the purpose of the evacuation of the pouch stricto            sensu from the second space, the second introduction means            and the second evacuation means being in the inactive closed            state,        -   Spacer means (11) interposed between the pouch stricto sensu            and the second casing, where it is ensured that the inner            surface of the second casing does not conceal any zone of            possible loss of integrity of the outer surface of the pouch            stricto sensu,        -   At least one selected tracer gas that is located,            respectively, in the first space or in the second space,            with a higher partial pressure than in the second space or            in the first space,        -   At least one colorimetric detector of at least one tracer            gas that is responsive to the concentration of at least one            tracer gas in the environment in which it is located, by            switching from a first color to a second color that is            different from the first color, with the at least one            colorimetric detector being located, respectively, in the            second space or in the first space,    -   In such a way as to be able, at any desired time after the pouch        is manufactured and at least just before the time when the pouch        stricto sensu is to be evacuated from the second casing and the        biopharmaceutical product or device is to be introduced into the        pouch stricto sensu, to interpret the visual assessment that the        at least one colorimetric detector is either of the first color,        signifying that the pouch stricto sensu has kept its integrity,        or of the second color, signifying that the pouch stricto sensu        has lost its integrity.

According to a first possible embodiment, at least one colorimetricdetector is housed in the first space that forms the pouch strictosensu, with the second space—outside of the pouch stricto sensu—havingan environment that comprises the tracer gas at a higher partialpressure than the environment of the first space. In this case,according to a variant embodiment, at least one colorimetric detectorthat is housed in the first space forming the pouch stricto sensu andthe biopharmaceutical product or device designed to to fill the pouchstricto sensu are of such natures that they can be in reciprocal contactwithout the biopharmaceutical quality of the product or device that willbe placed there subsequently being thereby affected. According toanother variant embodiment, the pouch with an incorporated and activeloss of integrity indicator comprises at least one separation wall thatis located in the first space that forms the pouch stricto sensu, havinga selective permeability, namely allowing the tracer gas to pass and notallowing the biopharmaceutical product or device to pass, whereby thisat least one separation wall delimits by itself or with the first casingat least a first compartment in which the at least one colorimetricdetector is housed.

According to a second possible embodiment, at least one colorimetricdetector is housed in the second space, outside of the pouch strictosensu, with the first space that forms the pouch stricto sensu having anenvironment that comprises the tracer gas at a higher partial pressurethan the environment of the second space outside of the pouch strictosensu. According to a variant embodiment, the pouch comprises at leastone separation wall that is located in the second space outside of thepouch stricto sensu that delimits by itself or with the first or thesecond casing at least one second compartment in which the at least onecolorimetric detector is housed.

According to the embodiments, the pouch stricto sensu is a 2D pouch or a3D pouch that comprises at least one gusset.

According to one embodiment, the spacer means (11) are porous materialor comprise porous material. For example, they come in the form of atleast one porous layer or at least one porous material. According to avariant embodiment, they come in the form of at least one porous layeror at least one porous material that structurally or functionallyintegrally covers the outer surface of the pouch stricto sensu, with thefirst means for introduction and the first means for evacuation of thepouch stricto sensu being in the inactive closed state, and the outersurface of the interior of the gusset of the pouch stricto sensu, when a3D pouch is involved.

According to the embodiments, the at least one colorimetric detector isarranged in a non-fixed or fixed manner in the space—first or secondspace—in which it is located, then being, in a variant embodiment, fixedor incorporated in the inner surface of the first casing, in the innersurface of the second casing, or with spacer means (11).

According to the embodiments, the first casing, on the one hand, and thesecond casing, on the other hand, comprise one or more integralsuperposed layers and incorporate at least one plastic material with ahigh-capacity gas barrier.

According to the embodiments, a tracer gas is selected from the groupthat comprises oxygen, carbon dioxide, and helium.

According to one embodiment, the at least one colorimetric detector isan autonomous element, lacking an internal energy source and outsideconnections.

According to one embodiment, the at least one colorimetric detector hasa large surface, so as to ensure simultaneously that it is responsive tothe tracer gas concentration in the environment in which it is locatedand that an observer can note visually if it has the first color or thesecond color.

According to one embodiment, the at least one colorimetric detector isat a localized site in the pouch.

According to one embodiment, the pouch with an incorporated and activeloss of integrity indicator comprises several colorimetric detectors atseveral sites in the pouch. In a variant embodiment, the colorimetricdetectors are at least essentially distributed in the pouch. Accordingto a first embodiment, the pouch comprises several colorimetricdetectors that are analogous in the same space, first space or secondspace outside of the pouch stricto sensu. According to a secondembodiment, the pouch with an incorporated and active loss of integrityindicator first comprises, on the one hand, at least one firstcolorimetric detector that is responsive to the concentration of a firsttracer gas, and, on the other hand, at least one second colorimetricdetector that is responsive to the concentration of a second firsttracer gas that is different from the first tracer gas, and, secondly,on the one hand, a first tracer gas in the second space with a higherpartial pressure than in the first space, and, on the other hand, asecond tracer gas in the first space with a higher partial pressure thanin the second space outside of the pouch stricto sensu.

According to one embodiment, a space—first or second space outside ofthe pouch stricto sensu—contains tracer gas, and the other space—secondspace outside of the pouch stricto sensu or first space—does notcomprise or substantially does not comprise tracer gas.

According to one embodiment, a colorimetric detector is generally flat,planar or curved, such as a pellet or a pseudo-pellet, or generally aline or a strip, while being rigid, flexible, or semi-flexiblesemi-rigid.

According to one embodiment, the pouch with an incorporated and activeloss of integrity indicator is flattened or essentially flattened onitself and thus easily suitable for storage, for shipping, or forhandling.

According to one characteristic, the second outer casing is able toallow an outside observer to identify—from outside of the outercasing—the color of at least one colorimetric detector. According to avariant embodiment, the second outer casing is transparent ortranslucent or comprises a transparent or translucent window forobserving the color of at least one colorimetric detector that islocated opposite or in the vicinity.

According to one embodiment, the second casing is flexible.

According to one embodiment, the pouch with an incorporated and activeloss of integrity indicator also comprises an outer protective packagingin which the second casing, in which the pouch stricto sensu is located,is housed.

According to a second aspect, the purpose of the invention is theapplication of a pouch with an incorporated and active loss of integrityindicator as it was just described, in which, just before the time whenthe pouch stricto sensu is evacuated from the second casing and thebiopharmaceutical product or device is introduced into the pouch strictosensu, the at least one colorimetric detector is being of the firstcolor, consisting in opening the second evacuation means of the secondcasing, to evacuate, extract, or remove the pouch stricto sensu from thesecond space, to open the first means for introducing the pouch strictosensu and to introduce the biopharmaceutical product or device into thefirst space, so as to provide a pouch stricto sensu that has all of itsintegrity containing the biopharmaceutical product or device, whichpouch stricto sensu and the biopharmaceutical product or device that itcontains then being suitable for use.

According to a third aspect, the purpose of the invention is a pouchstricto sensu that has its full guarantee of integrity, speciallydesigned to contain a biopharmaceutical product or device, created froma pouch with an incorporated and active loss of integrity indicator asit was just described, in which, with the at least one colorimetericdetector being of the first color, the pouch stricto sensu wasevacuated, extracted, or removed from the second casing, with the pouchstricto sensu then being suitable for use.

According to a possible variant embodiment, at least one colorimetricdetector is housed in the first space of the pouch stricto sensu.

According to a fourth aspect, the purpose of the invention is a processfor the production of a pouch with an incorporated and active loss ofintegrity indicator as it was described, in which:

-   -   A first flexible casing, made of at least one non-porous plastic        material with a high-capacity gas barrier, delimiting a first        space, forming a pouch stricto sensu that can accommodate the        biopharmaceutical product or device when desired but devoid of        the latter, comprising, on the one hand, first introduction        means for the purpose of subsequent introduction, when desired,        of the biopharmaceutical product or device into the pouch        stricto sensu, and, on the other hand, first evacuation means        for the purpose of subsequent evacuation, when desired, of the        biopharmaceutical product or device of the pouch stricto sensu,        is provided,    -   A second casing made of at least one non-porous plastic material        with a high-capacity gas barrier, comprising, on the one hand,        second introduction means for the purpose of introducing the        pouch stricto sensu into the second space, and, on the other        hand, second evacuation means for the purpose of the evacuation        of the pouch stricto sensu from the second space, is provided,    -   Spacer means (11) are provided,    -   At least one selected tracer gas is provided,    -   At least one colorimetric detector of at least one tracer gas        that is responsive to the concentration of at least one tracer        gas in the environment in which it is located, by switching from        a first color to a second color that is different from the first        color, is provided,    -   The pouch stricto sensu is introduced into the second casing,        and spacer means (11) are interposed between them in such a way        that the inner surface of the second casing does not conceal any        zone of possible loss of integrity of the outer surface of the        pouch stricto sensu,    -   The at least one selected tracer gas is introduced,        respectively, into the first space or into the second space        outside of the pouch stricto sensu, with a higher partial        pressure than in the second space outside of the pouch stricto        sensu or in the first space, and the at least one colorimetric        detector of the at least one tracer gas is placed in the second        space outside of the pouch stricto sensu or in the first space,        respectively,    -   And, finally, the pouch stricto sensu and the second casing are        closed.

According to the embodiments, the at least one colorimetric detector isprovided in the pouch stricto sensu, and the at least one tracer gas isintroduced into the second space outside of the pouch stricto sensu at ahigher partial pressure than the environment of the first space, and theat least one colorimetric detector is provided in the second casingoutside of the pouch stricto sensu, and the at least one tracer gas isintroduced into the pouch stricto sensu at a higher partial pressurethan the environment of the first space.

According to one embodiment, the at least one tracer gas is introducedinto a space—first space or second space outside of the pouch strictosensu—and the at least one tracer gas is not introduced without theother space—second space outside of the pouch stricto sensu or firstspace.

According to one embodiment, air is purged from the space that containstracer gas at a lower partial pressure or without tracer gas.

According to the embodiments, the at least one colorimetric detector isprovided in a non-fixed way in the space—first or second space—in whichit should be located or in contrast in a fixed way in the space—first orsecond space—in which it should be located, by fixing it orincorporating it in the inner surface of the first casing, in the innersurface of the second casing, or in the spacer means.

According to one embodiment, several colorimetric detectors are placedat several sites in the pouch. According to one variant embodiment,several analogous colorimetric detectors are placed in the same space,first space, or second space outside of the pouch stricto sensu.According to another variant embodiment, at least one colorimetricdetector is placed in the first space, and at least one colorimetricdetector is placed in the second space outside of the pouch strictosensu.

According to one embodiment, the second casing in which the pouchstricto sensu is located is placed in an outer protective packaging.

According to a fifth and final aspect, the purpose of the invention is aprocess relative to pouches stricto sensu that is specially designed tocontain a biopharmaceutical product or device and having to exhibit itsfull guarantee of integrity, with the process comprising, on amanufacturing site, initial operations that consist in manufacturing thepouch stricto sensu, on a site of use, of final operations that consistin using the pouch stricto sensu by placing there, when desired, thebiopharmaceutical product or device and by ensuring the desiredtreatment, and intermediate operations of storage, shipping, andhandling, characterized by:

-   -   The production, on the manufacturing site, of a pouch with an        incorporated and active loss of integrity indicator that        comprises the pouch stricto sensu, as it was described,    -   The shipping of the pouch with an incorporated and active loss        of integrity indicator that comprises the pouch stricto sensu        from the manufacturing site to the site of use, by means of, if        necessary, operations of storage and handling,    -   And, at least on the site of use and just before the time when        the pouch stricto sensu is evacuated from the second casing and        the biopharmaceutical product or device is introduced into the        pouch stricto sensu, the visual examination of the color of the        at least one colorimetric detector so as to note whether the at        least one colorimetric detector is of the first color or of the        second color, with the pouch stricto sensu being used for the        biopharmaceutical product or device only if the at least one        colorimetric detector is of the first color, while if the at        least one colorimetric detector is of the second color, the        pouch stricto sensu is not used for the biopharmaceutical        product or device.

According to one characteristic of this process, there is a stage inwhich the colorimetric detector keeps the first color or switches fromthe first color to the second color that occurs in the background duringthe intermediate operations of storage, shipping, and handling.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the invention will now be described usingdrawings, in which:

FIGS. 1A, 1B and 1C are three views of a 3D-type pouch stricto sensu,namely, respectively, an exploded and diagrammatic view of the pouchbefore production, an elevation view of the pouch folded flat, and aperspective view of the pouch by volume;

FIGS. 2 and 3 are two views of a first embodiment of the pouch with anincorporated loss of integrity indicator that is active per se and afterthe manufacturing of the pouch and at least before the time when abiopharmaceutical product or device is introduced therein, comprising apouch stricto sensu, a second outer casing, spacer means, a tracer gas,and a colorimetric detector of the tracer gas, namely an elevation viewand a cutaway view through a transverse plane, along the line III-III ofFIG. 2; in this first embodiment, the colorimetric detector is housed inthe pouch stricto sensu;

FIGS. 4 and 5 are two views that are analogous to FIGS. 2 and 3 of asecond embodiment of a pouch with an incorporated and active loss ofintegrity indicator; in this second embodiment, the colorimetricdetector is housed in the second space that is delimited by the secondcasing, outside of the pouch stricto sensu;

FIGS. 6 and 7 are two views that are analogous to FIGS. 2 and 4 and twoother embodiments of a pouch with an incorporated and active loss ofintegrity indicator, comprising several colorimetric detectors,respectively in the second space that is delimited by the second casing,outside of the pouch stricto sensu and at the same time in the secondspace that is delimited by the second casing, outside of the pouchstricto sensu and in the pouch stricto sensu.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Flexible 3D pouches 1, specially designed to contain a biopharmaceuticalfluid as defined above, are known in the biopharmaceutical field.

Such a pouch 1 is called “pouch stricto sensu” here, meaning by thisexpression that it constitutes per se the pouch that is designed tocontain biopharmaceutical fluid, whereas this pouch stricto sensu isincorporated in a more complex unit called “pouch with an incorporatedand active loss of integrity indicator” 2.

Such a pouch stricto sensu 1 can have a large volume of at least 50liters, up to 1,000 liters, and even more, which means that it isdescribed as 3D. Such a pouch is described in, for example, theInternational Application WO00/04131, whereby this embodiment does notexclude others. Such a pouch is also marketed by the Sartorius Companyunder the trademark FLEXEL® 3D.

Such a pouch stricto sensu 1 comprises in particular primary walls 3 andtwo side gussets 4, with the different constituent parts being welded toone another along seam lines 5 in such a way as to form a casing, called“first casing,” also designated by the reference 1.

The pouch stricto sensu 1 is closed, flexible and made from non-porousplastic material with a high-capacity gas barrier, comprising one ormore integral superposed layers that incorporate at least one plasticmaterial with a high-capacity gas barrier, such as EVOH.

The pouch stricto sensu 1 delimits a first space 6, of suitable volume,able to accommodate the biopharmaceutical product when this is desired.

The pouch stricto sensu 1 comprises first introduction means 7 for thepurpose of the introduction, when this is desired, of thebiopharmaceutical product into the first space 6.

The pouch stricto sensu 1 also comprises first evacuation means for thepurpose of the evacuation, when this is desired, of thebiopharmaceutical product of the first space 6.

Such first introduction means and first evacuation means can come in theform of ports, arranged to be open or closed, based on requirements.

Such a pouch stricto sensu 1 is typically found in two end states: astate that is folded flat and a state that is deployed unfolded. It canbe deformed to switch from one to the other of these states or is foundin any intermediate state.

Such a pouch stricto sensu 1 is typically designed to be combined with arigid container that contains the pouch from the outside. Such acontainer is described in a possible variable embodiment in the documentEP-A-1012073 and also marketed by the Sartorius Company under thetrademark PALLETTANK®.

Such a pouch stricto sensu 1 is typically designed to be combined with arigid container.

The operating process of such pouches stricto sensu 1 consists, on agiven manufacturing site, in implementing initial operations thatconsist in manufacturing the pouch stricto sensu 1 and, on a site ofuse, most often different and distant from the manufacturing site, inproducing a certain number of so-called final operations that consist inusing the pouch stricto sensu 1, i.e., placing there, at the time whenthis is desired, a biopharmaceutical product, and then by ensuring thedesired treatment. This treatment is storage, shipping, or any otherfunctional treatment such as mixing, aeration, or the like.

Between the initial operations and the final operations, intermediateoperations, such as, typically, storage, shipping or handling, takeplace. These intermediate operations can extend over a rather longperiod, for example several months, and even several years, involving,for example, storage.

Although the pouches stricto sensu 1 are produced from non-porousplastic material with a high-capacity gas barrier and although the seamlines 5 are a priori airtight, it is essential to ensure that each pouchhas the desired seal, not only during its manufacturing, but also, aftermanufacturing, at least just before the time when the biopharmaceuticalproduct is introduced thereinto. Failing this, the quality of thebiopharmaceutical product could be affected and the biopharmaceuticalproduct made unusable, or the pouch stricto sensu could be sodeteriorated that it could not perform its function. Such situations areparticularly serious and troublesome, whereas the biopharmaceuticalproduct that is placed in the pouch stricto sensu is expensive and rarein large amounts.

A pouch stricto sensu 1 whose possession of the desired seal has beenverified is called a pouch stricto sensu 1 that has its full guaranteeof integrity. A pouch that does not have the desired seal is called apouch stricto sensu 1 that has lost its integrity.

The integrity of the pouch stricto sensu 1 is essential so that thelatter performs its function as an airtight and sterile container,maintaining the sterility being a critical factor in thebiopharmaceutical processes.

The integrity of a pouch stricto sensu 1 can be affected as a result ofmanufacturing defects (presence of one or more small holes in the pouchor deficient seam lines 5, for example) or as a result duringintermediate operations of storage, shipping or handling, with the riskbeing higher as these intermediate operations extend over a long periodof time.

So as to be able, at least on the site of use and just before the timeprovided, to introduce the biopharmaceutical product into the pouchstricto sensu 1, the process relative to the pouches stricto sensu ismodified, in accordance with the invention.

This process first comprises the production, on the manufacturing site,of a pouch stricto sensu and the manufacturing, starting from thelatter, of a pouch with an incorporated and active loss of integrityindicator 2.

This process next comprises the shipping of this pouch with anincorporated and active loss of integrity indicator 2 from themanufacturing site to the site of use, by means of, if necessary,operations of storage and handling, all of these operations constitutingthe so-called intermediate operations.

This process finally comprises—at least on the site of use and justbefore the time when the biopharmaceutical product is introduced intothe pouch stricto sensu 1—the checking of the integrity of the pouchstricto sensu 1, the latter being used for the biopharmaceutical productonly if the integrity is guaranteed, while if the integrity cannot beguaranteed, the pouch stricto sensu 1 is not used for thebiopharmaceutical product.

According to the invention, this checking of the integrity of the pouchstricto sensu 1 is achieved in a reliable, easy and quick way, withoutthe necessity for a heavy or complex dedicated device, or difficult ordelicate operations, without the necessity for having recourse tospecialized personnel, especially and exclusively dedicated to checkingthe integrity, and without the necessity for having to test the pouchpositively for ensuring its integrity, with the loss of integrity beingrevealed automatically, and therefore without the necessity—when thepouch is part of a large number of pouches—of having to test each pouchpositively.

In addition, this checking is carried out after an operating phase thattakes place in the background during the intermediate operations ofstorage, shipping, and handling, and without the necessity forintervention.

The invention applies not only in the case where the pouch stricto sensu1 is a 3D pouch, but also in the case of a 2D pouch.

The invention also applies not only in the case of a biopharmaceuticalproduct, but also in the case of a biopharmaceutical device, as definedabove.

The pouch 2 with an incorporated loss of integrity indicator, that isactive per se—and after the manufacturing of the pouch and at leastbefore the time when a biopharmaceutical product or device is introducedthereinto, as it is manufactured, and before all use—first of allcomprises the pouch stricto sensu 1.

The pouch stricto sensu 1 is then closed and devoid of abiopharmaceutical product or device. Its first introduction means 7 andits first evacuation means are in the inactive closed state.

The pouch 2 with an incorporated and active loss of integrity indicatornext comprises a second outer casing 8, with the pouch stricto sensu 1being inside.

The second casing 8 is closed, produced from at least one non-porousplastic material with a high-capacity gas barrier, and, in theembodiment shown, flexible. For example, the second casing 8 comprisesone or more integral superposed layers that incorporate at least oneplastic material with a high-capacity gas barrier, such as EVOH.

The second casing 8 delimits a second space 9, in which the pouchstricto sensu 1 is located.

It is by this arrangement that the pouch 2 makes possible the detectionof a possible loss of integrity of the pouch stricto sensu 1.

The second casing 8 also comprises second introduction means 10 havingallowed the preliminary introduction of the pouch stricto sensu 1 intothe second space 9, such as an opening that is next closed by a seamline.

The second casing 8 also comprises second evacuation means (extractionor removal) for the purpose of the evacuation (extraction or removal) ofthe pouch stricto sensu 1 from the second space 9, such as a tearing ofthe second casing 8.

In the pouch 2 with an incorporated and active loss of integrityindicator, the second introduction means 10 and the second evacuationmeans are in the inactive closed state.

The pouch 2 with an incorporated and active loss of integrity indicatornext comprises spacer means 11, interposed between the stricto sensupouch 1 and the second casing 8.

These spacer means 11 are where it is ensured that the inner surface 8 aof the second casing 8 does not conceal any zone of possible loss ofintegrity of the outer surface la of the pouch stricto sensu 1.

The pouch 2 with an incorporated and active loss of integrity indicatornext comprises at least one selected tracer gas, and at least onecolorimetric detector 12 of this tracer gas.

Such a colorimetric detector 12 is responsive to the concentration ofthe tracer gas in the environment in which it is located, by switchingfrom a first color to a second color that is different from the firstcolor.

Such a tracer gas is selected from, for example, the group thatcomprises oxygen, carbon dioxide, and helium. Such a colorimetricdetector 12 that is adapted to such a tracer gas is accessible to oneskilled in the art. Such a colorimetric detector 12 is an autonomouselement, lacking any internal energy source and outside connections.

Such a colorimetric detector 12 has a large surface, so as to ensuresimultaneously that it is effectively responsive to the tracer gasconcentration in the environment in which it is located and to make itpossible for an observer to be able to visually note if it has the firstcolor or the second color.

According to the embodiments, such a colorimetric detector 12 isgenerally flat, planar or curved, such as a pellet or a pseudo-pellet,or generally a line or a strip, while being rigid, flexible, orsemi-flexible semi-rigid.

The pouch 2 with an incorporated and active loss of integrity indicatornext comprises spacer means, is flattened or essentially flattened onitself, and thus is easily suitable for storage, for shipping, or forhandling, in particular in the operations that are described asintermediate operations above.

In general, the tracer gas is respectively in the first space 6 or inthe second space 9 outside of the pouch stricto sensu 1, with a higherpartial pressure than in the second space 9 outside of the pouch strictosensu 1 or in the first space 6. As a variant, a space—first or secondspace outside of the pouch stricto sensu 6, 9—contains tracer gas, andthe other space—second space outside of the pouch stricto sensu or firstspace 9, 6—does not comprise or substantially does not comprise tracergas.

Whereas the tracer gas is respectively in the first space 6 or in thesecond space 9 outside of the pouch stricto sensu 1, the colorimetricdetector 12 is respectively located in the second space 9 outside of thepouch stricto sensu 1 or in the first space 6.

Thus, at any time desired after the manufacturing of the pouch 2 with anincorporated and active loss of integrity indicator—and at least justbefore the time when the pouch stricto sensu 1 is used (introduction ofthe biopharmaceutical product or device into the pouch stricto sensu1)—an outside observer can note de visu the color of the colorimetricdetector 1.

This observer interprets this visual assessment in the following manner:if the colorimetric detector 12 is of the first color, the pouch strictosensu 1 has all of its integrity. If the colorimetric detector 12 is ofthe second color, the pouch stricto sensu 1 has lost its integrity.

“Interpreting” is defined as the fact of providing for the pouch strictosensu 1, relative to its integrity, a meaning that originates from theassessment of the color of the colorimetric detector 12. Thiscorrespondence of the color of the colorimetric detector 12

integrity of the pouch stricto sensu 1 is one-to-one, which leaves nodoubt as to whether the pouch stricto sensu 1 has integrity or not, inthe sole view of the color of the colorimetric detector 12, without thenecessity for operations, handling, computations, calculations, . . .

The second casing 8 is designed in such a way as to make it possible foran outside observer to identify—from the outside of this casing 8—thecolor of the colorimetric detector 12 that is located inside. For thispurpose, the second casing 8 is, according to the embodiments,transparent or translucent, or it comprises a transparent or translucentwindow for observing the color of the colorimetric detector 12 that islocated opposite to or in the vicinity of this window.

According to one possible embodiment, an outer protective packaging inwhich the pouch 2 with an incorporated and active loss of integrityindicator is housed is provided, it being understood that the secondcasing 8 can itself be a part of the packaging and the protection of thepouch stricto sensu 1.

In a first embodiment that is illustrated by FIGS. 2 and 3, thecolorimetric detector 12 is housed in the first space 6 that forms thepouch stricto sensu 1, while the second space 9 outside of the pouchstricto sensu 1 has an environment that comprises the tracer gas at ahigher partial pressure than the environment of the first space 6.

According to a first variant of this first embodiment, the colorimetricdetector 12 and the biopharmaceutical product or device are of suchnatures that they can be in reciprocal contact without thebiopharmaceutical quality of the product or device being therebyaffected.

According to a first variant of this same first embodiment, the pouch 2comprises a separation wall located in the first space 6 that forms thepouch stricto sensu 1. This separation wall has a selectivepermeability, namely allowing the tracer gas to pass and not allowingthe biopharmaceutical product or device to pass. This separation walldelimits, by itself alone or in combination with the first casing 1, afirst compartment in which the colorimetric detector 12 is housed.

In a second embodiment that is illustrated by FIGS. 4 and 5, thecolorimetric detector 12 is housed in the second space 9, outside of thepouch stricto sensu 1, with the first space 6 then having an environmentthat comprises the tracer gas at a higher partial pressure than theenvironment of the second space 9, outside of the pouch stricto sensu 1.

According to a variant of this second embodiment, the pouch 2comprises—outside of the pouch stricto sensu 1—a separation wall that islocated in the second space 9, outside of the pouch stricto sensu 1.This separation wall delimits—by itself alone or in combination with thefirst casing 1 or with the second casing 8—a second compartment in whichthe colorimetric detector 12 is housed.

According to one embodiment, the spacer means 11 are or comprise porousmaterial. For example, they come in the form of at least one porouslayer or at least one porous material, structurally or functionallyintegrally covering the outer surface la of the pouch stricto sensu 1.According to the embodiments, such a porous layer or at least one porousmaterial is produced in fabrics, in non-woven fabrics, in PE, in PP, inPTFE, or the like, whereby this list is not limiting. The purpose of theconstruction arrangement that is indicated is that the lower surface 8 aof the second casing 8, even if it is against the outer surface 1 a ofthe first casing 1, does not conceal any zone of possible loss ofintegrity of the pouch stricto sensu 1, with the porous layer or atleast one porous material of the space means 11 being interposed betweenthese two surfaces 1 a and 8 a.

In addition, the spacer means 11, thus produced, structurally orfunctionally integrally cover the first introduction means 7 and thefirst evacuation means of the pouch stricto sensu 1, being in theinactive closed state.

Also, the spacer means 11, thus produced, structurally or functionallyintegrally cover the outer surface of the interior of the gusset 4 ofthe pouch stricto sensu 1 when the latter is a 3D pouch.

Structural integral covering is defined as the fact that the spacermeans 11 structurally integrally cover the pouch stricto sensu 1.Functional integral covering is defined as the fact that the spacermeans 11, without necessarily integrally and structurally covering thepouch stricto sensu 1, ensure the spacing function over the entiresurface of the pouch stricto sensu 1.

The pouch 2 with an incorporated and active loss of integrity indicatorcan be the object of various variant embodiments.

According to the embodiments, the colorimetric detector 12 is arrangedin a non-fixed or, in contrast, a fixed way in the space—first space 6or second space 9—in which it is located. In the second case, thecolorimetric detector 12 is, for example, fixed or incorporated in theinner surface 1 b of the first casing 1, or in the inner surface 8 a ofthe second casing 8, or else in the spacer means 11.

According to the embodiments, the colorimetric detector 12 is at alocalized site in the pouch 2 with an incorporated and active loss ofintegrity indicator or else several colorimetric detectors 12 areprovided at several sites in the pouch 2, in particular at leastessentially distributed in the pouch in such a way as to be locatedclose enough for any possible loss of integrity, with such a structureproviding maximum safety and efficiency.

For example, several analogous colorimetric detectors 12 can be providedin the same space, namely the first space 1 or the second space 9outside of the pouch stricto sensu 1, as it is shown in FIG. 6.

Or, there may be provided one (or more) first colorimetric detector(s)12 a located in the first space 1 and one (or more) second colorimetricdetector(s) 12 b located in the second space 9 outside of the pouchstricto sensu 1, as it is shown in FIG. 7. In such an embodiment, thefirst detector 12 a is responsive to a first tracer gas, and the seconddetector 12 b is responsive to a second tracer gas, with these twotracer gases being, of course, different.

A pouch 2 with an incorporated and active loss of integrity indicator isimplemented in the following manner: just before the time when the pouchstricto sensu 1 is evacuated, extracted, or removed from the secondcasing 8 and the biopharmaceutical product or device is introduced intothe pouch stricto sensu 1, with the colorimetric detector 12 being ofthe first color, which means that the pouch stricto sensu 1 has all ofits integrity, the second evacuation means of the second casing 8 areopened, the pouch stricto sensu 1 is evacuated, extracted, or removedfrom the second space 9, the first introduction means 7 of the pouchstricto sensu 1 are opened, and the biopharmaceutical product or deviceis introduced into the first space 1. Thus, a pouch stricto sensu 1 thathas all of its integrity and that contains the biopharmaceutical productor device is provided. This pouch stricto sensu 1 and thebiopharmaceutical product or device that it contains are then suitablefor the desired use.

In the case where the colorimetric detector 1 is housed in the pouchstricto sensu 1, this pouch stricto sensu 1 that results from theimplementation of the pouch 2 with an incorporated and active loss ofintegrity indicator comprises the colorimetric detector 12 in question,with the latter being of the first color. As indicated above, the pouchstricto sensu 1 has been evacuated, extracted, or removed from thesecond casing 8 and is then suitable for use.

The process for production of a pouch 2 with an incorporated and activeloss of integrity indicator is as follows.

First of all, a first casing 1 that is devoid of biopharmaceuticalproduct or device, a second casing 8, spacer means 11, tracer gas, and acolorimetric detector 12 corresponding to the tracer gas are provided.

Then, the pouch stricto sensu 1 is introduced into the second casing 8,and the spacer means 11 are interposed between them as disclosed.

Also, the tracer gas is introduced into the space 6 or 9 outside of thepouch stricto sensu 1 before accommodating it, and the colorimetricdetector 12 is placed in the other space 9 outside of the pouch strictosensu 1 or 6.

Finally, the pouch stricto sensu 1 and the second casing 8 are closed.

This process may be the object of different variant embodiments thatcorrespond to the variants of the pouch 2.

Thus, according to the embodiments, the colorimetric detector 12 isprovided in the pouch stricto sensu 1, and the tracer gas is introducedinto the second space 9 outside of the pouch stricto sensu 1 at a higherpartial pressure than the environment of the first space 1, or,conversely, the colorimetric detector 12 is provided in the secondcasing 8, outside of the pouch stricto sensu 1, and the tracer gas isintroduced into the pouch stricto sensu 1 at a higher partial pressurethan the environment of the second space 9, outside of the pouch strictosensu 1.

According to one embodiment, the tracer gas is introduced into aspace—first space 6 or second space 9 outside of the pouch stricto sensu1, and the tracer gas is not introduced into the other space—secondspace 9 outside of the pouch stricto sensu 1 or first space 6.

According to one embodiment, the air is purged from the space 6, 9containing the tracer gas at a lower partial pressure or without tracergas.

According to the embodiments, the colorimetric detector 12 is providedin the space—first or second space outside of the pouch stricto sensu 6or 9—in which it is to be located, in a non-fixed way or, in contrast, afixed way, for example by fixing it or by incorporating it in the innersurface la of the first casing 1, in the inner surface 8 a of the secondcasing 8, or in the spacer means 11.

According to one embodiment, several colorimetric detectors 12 areplaced at several sites in the pouch 2, namely several analogouscolorimetric detectors in the same space, first space 6 or second space9 outside of the pouch stricto sensu 1, or a first colorimetric detector12 a in the first space 6 and a second colorimetric detector 12 b in thesecond space 9 outside of the pouch stricto sensu 1.

Also, according to one embodiment, the process comprises a stage inwhich the second casing 8, in which the pouch stricto sensu 1 islocated, is placed in an outer protective packaging.

The operating process is therefore such that it comprises the followingstages:

-   -   The production, on the manufacturing site, of a pouch 2 with an        incorporated and active loss of integrity indicator that        comprises the pouch stricto sensu 1,    -   The shipping of the pouch 2 from the manufacturing site to the        site of use, by means of, if necessary, operations of storage        and handling,    -   And, at least on the site of use and just before the time when        the pouch stricto sensu 1 is evacuated, extracted, or removed        from the second casing 8 and the biopharmaceutical product or        device is introduced into the pouch stricto sensu 1, the visual        examination by the outside observer of the color of the        colorimetric detector 12 so as to note whether it is of the        first color or the second color. The pouch stricto sensu 1 is        used for the biopharmaceutical product or device only if the        colorimetric detector 12 is of the first color, while if the        colorimetric detector 12 is of the second color, the pouch        stricto sensu 1 is not used for the biopharmaceutical product or        device.

The colorimetric detector 12 keeps the first color or switches from thefirst color to the second color in the background during theintermediate operations of storage, shipping, and handling.

1. A method for producing a pouch with an incorporated and active loss of integrity indicator, the pouch including: a first flexible, closed, inner casing made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a first space, forming a first space pouch configured to accommodate a fluid biopharmaceutical product or device, the inner casing including a first introduction means for introducing the biopharmaceutical product or device into the first space pouch, and a first evacuation means for subsequently evacuating the biopharmaceutical product or device from the first space pouch, the first introduction means and the first evacuation means being in an inactive closed state; a second, closed, outer casing made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a second space in which the first space pouch is located for detection of a loss of integrity of the first space pouch including second introduction means for preliminarily introducing the first space pouch into the second space, and second evacuation means for evacuating the first space pouch from the second space, the second introduction means and the second evacuation means being in the inactive closed state; a spacer means interposed between the first space pouch and the second casing, an inner surface of the second casing being configured to not conceal a zone of loss of integrity of an outer surface of the first space pouch, the spacer means being or including porous material; at least one tracer gas that is located respectively in one of the first space or in the second space, the second space being outside of the first space pouch, having a higher partial pressure than a pressure in the other of the first space and the second space; and an incorporated loss of integrity indicator including at least one colorimetric detector that detects the at least one tracer gas, the at least one colorimetric detector being responsive to a concentration of the tracer gas in an environment in which the detector is located, by switching from a first color to a second color that is different from the first color, the at least one colorimetric detector being located in one or more of the second space outside of the first space pouch and in the first space, the colorimetric detector being configured to visually indicate one of the first color, signifying that the first space pouch has kept its integrity, and the second color, signifying that the first space pouch has lost its integrity, after the pouch with the incorporated loss of integrity indicator is manufactured and at least before the time when the first space pouch is evacuated, extracted, or removed from the second casing and the biopharmaceutical product or device is introduced into the first space pouch, and the colorimetric detector being configured to detect the at least one tracer gas when the first space pouch is devoid of the biopharmaceutical product or device and when the second, closed, outer casing is maintained in a closed state, the method comprising: providing the first flexible casing made of the at least one non-porous plastic material with the high-capacity gas barrier, delimiting the first space, forming the first space pouch that can accommodate the biopharmaceutical product or device, the first flexible casing including the first introduction means and the first evacuation means; providing the second casing made of the at least one non-porous plastic material with the high-capacity gas barrier, the second casing including the second introduction means and the second evacuation means, providing the spacer means; providing the at least one selected tracer gas; providing the at least one colorimetric detector of the at least one tracer gas that is responsive to the concentration of the at least one tracer gas in the environment in which the colorimetric detector is located, by switching from the first color to the second color that is different from the first color; introducing the first space pouch into the second casing; interposing the spacer means between the first space pouch and the second casing in such a way that the inner surface of the second casing does not conceal the zone of possible loss of integrity of the outer surface of the inner space pouch; and introducing the at least one selected tracer gas into the one of the first space and the second space outside of the inner space pouch, with the higher partial pressure than a pressure in the other of the first space and the second space outside of the inner space pouch, the at least one colorimetric detector of the at least one tracer gas being placed in one of the first space and the second space outside of the inner space pouch; and closing the inner space pouch and the second casing.
 2. The method according to claim 1, further comprising: providing the at least one colorimetric detector in the first space pouch; and introducing the at least one tracer gas into the second space outside of the first space pouch at the higher partial pressure than the environment of the first space.
 3. The method according to claim 2, further comprising: providing the at least one colorimetric detector in the second casing outside of the first space pouch; and introducing the at least one tracer gas into the first space pouch at the higher partial pressure than the environment of the first space.
 4. The method according to claim 1, further comprising: introducing the at least one tracer gas in one of the first space and the second space, the second space being outside of the first space pouch, wherein the at least one tracer gas is not introduced within the other of the first space and the second space.
 5. The method according to claim 1, further comprising: purging air from the one of the first space and the second space that contains the at least one tracer gas at a lower partial pressure or from the one of the first space and the second space that is without the at least one tracer gas.
 6. The method according to claim 1, further comprising: providing the at least one colorimetric detector in a non-fixed way in the first space or the second space.
 7. The method according to claim 1, further comprising: providing the at least one colorimetric detector in a fixed way in the one of the first space and the second space by fixing the at least one colorimetric detector or incorporating the at least one colorimetric detector in the inner surface of the first casing, in the inner surface of the second casing, or in the spacer means.
 8. The method according to claim 1, further comprising: placing a plurality of colorimetric detectors at a plurality of sites in the pouch.
 9. The method according to claim 8, further comprising: placing a plurality of analogous ones of the colorimetric detectors in the same space, the first space, or the second space.
 10. The method according to claim 8, further comprising: placing at least one of the colorimetric detectors in the first space, and at least one of the colorimetric detectors in the second space.
 11. The method according to claim 1, wherein the second casing, in which the first space pouch is located, is placed in an outer protective packaging.
 12. A method relative to pouches specially designed to contain a biopharmaceutical product or device and having to exhibit a full guarantee of integrity, the method comprising: manufacturing the pouch including the inner space pouch configured to receive the biopharmaceutical product or device, and by ensuring the desired treatment, and intermediate operations of storage, shipping, and handling, producing the pouch with the incorporated and active loss of integrity indicator according to claim 1; shipping the pouch with the incorporated and active loss of integrity indicator that comprises the inner space pouch from the manufacturing site to a site of use by operations of storage and handling; and at least on the site of use and just before the time when the inner space pouch is evacuated, extracted, or removed from the second casing and the biopharmaceutical product or device is introduced into the inner space pouch, examining the color of the at least one colorimetric detector to determine whether the at least one colorimetric detector is the first color or the second color, the inner space pouch being used for the biopharmaceutical product or device only when the at least one colorimetric detector is the first color, and when the at least one colorimetric detector is the second color, the inner space pouch is not used for the biopharmaceutical product or device.
 13. The method according to claim 12, further comprising: maintaining the first color at the colorimetric detector or switching from the first color to the second color at the colorimetric detector that occurs in the background during intermediate operations of storage, shipping, and handling.
 14. A method for producing a pouch with an incorporated and active loss of integrity indicator, the method comprising: providing a first flexible casing made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a first space, forming a first space pouch configured to accommodate a biopharmaceutical product or device, the first flexible casing including a first introduction means and a first evacuation means; providing a second casing made of at least one non-porous plastic material with a high-capacity gas barrier, the second casing including a second introduction means, and a second evacuation means, providing a spacer means; providing at least one selected tracer gas; providing at least one colorimetric detector of the at least one tracer gas that is responsive to a concentration of the at least one tracer gas in an environment in which the colorimetric detector is located, by switching from a first color to a second color that is different from the first color; introducing the first space pouch into the second casing; interposing the spacer means between the first space pouch and the second casing in such a way that an inner surface of the second casing does not conceal a zone of possible loss of integrity of an outer surface of an inner space pouch; and introducing the at least one selected tracer gas into the one of the first space and the second space outside of the inner space pouch, with a higher partial pressure than a pressure in the other of the first space and the second space outside of the inner space pouch, the at least one colorimetric detector of the at least one tracer gas being placed in one of the first space and the second space outside of the inner space pouch; and closing the inner space pouch and the second casing.
 15. A method for producing a pouch with an incorporated and active loss of integrity indicator, the method comprising: providing a first flexible casing made of at least one non-porous plastic material with a high-capacity gas barrier, delimiting a first space, forming a first space pouch configured to accommodate a biopharmaceutical product or device, the first flexible casing including a first introduction system and a first evacuation system; providing a second casing made of at least one non-porous plastic material with a high-capacity gas barrier, the second casing including a second introduction system, and a second evacuation system, providing a spacer; providing at least one selected tracer gas; providing at least one colorimetric detector of the at least one tracer gas that is responsive to a concentration of the at least one tracer gas in an environment in which the colorimetric detector is located, by switching from a first color to a second color that is different from the first color; introducing the first space pouch into the second casing; interposing the spacer between the first space pouch and the second casing in such a way that an inner surface of the second casing does not conceal a zone of possible loss of integrity of an outer surface of an inner space pouch; and introducing the at least one selected tracer gas into the one of the first space and the second space outside of the inner space pouch, with a higher partial pressure than a pressure in the other of the first space and the second space outside of the inner space pouch, the at least one colorimetric detector of the at least one tracer gas being placed in one of the first space and the second space outside of the inner space pouch; and closing the inner space pouch and the second casing. 